Abstract Background Refractory or "no option" angina (RA) is a debilitating condition with increasing global prevalence. Exogenous transduction of vascular endothelial growth factor (VEGF) induces angiogenesis and improves perfusion of ischemic myocardium in preclinical studies. XC001 (AdVEGFXC1) is a novel adenoviral-5 vector expressing the three major isoforms of VEGF (-121, -165, -189) in ratios shown to enhance potency and improve safety. Purpose EXACT is a single-arm, multicenter, open-label, phase 2 trial to explore the safety, tolerability, and preliminary efficacy of trans-epicardial delivery of XC001 to improve exercise capacity and ischemic burden in RA patients. Methods Patients were required to have stable Canadian Cardiovascular Society (CCS) class II-IV angina on maximally tolerated medical therapy with exercise limited by angina after 90 but before 540 seconds on a modified Bruce protocol, demonstrable ischemia on stress positron emission tomography (PET) and lack revascularization options. XC001 (1x1011 viral particles) was injected directly into ischemic myocardium via surgical transthoracic epicardial access. The primary outcome was safety by adverse event monitoring. Efficacy assessments included difference from baseline to six months in total exercise time (TET), myocardial ischemia by PET, angina class, angina frequency, and quality of life. Results Thirty-two patients (mean/median ages of 64/64, 34% female) were enrolled at 13 sites between March 2021 and July 2022. Median anti-anginal use was 3, 75% had prior revascularization with CABG and 88% with PCI. Fifty-five serious adverse events (SAEs) were observed in 21 patients (66%). None were attributed to study drug. Twenty-one SAEs in 14 patients were related to the surgical procedure, all of which were expected. One non-CV death occurred in month 3 following respiratory infection (Covid) deemed unrelated to surgery or study drug. Compared to baseline, total exercise time at 6-months increased by 85.5 seconds (95% CI 31.3-139.7) [Figure 1A] while total myocardial ischemic deficit in the treated region on PET decreased by 14.4% (95% CI, 3.01–25.73) [Figure 1B]. Angina frequency and nitroglycerin use measured during a two-week diary decreased by 6.6 episodes (95% CI, 3.5–9.7) and 4.1 doses (95% CI, 1.3–6.9), respectively. Canadian Cardiovascular Society angina grade decreased from 3.1 to 1.8, mean difference 1.3 classes (95% CI, 1.0–1.6) [Figure 2] while Seattle Angina Questionnaire Frequency score improved from 41.3 to 67.4, mean difference of 26.1 (95% CI, 16.3–35.9). Conclusions VEGF gene therapy with XC001 administered via minimally invasive epicardial delivery appears safe and well tolerated. Improvements in objective and subjective measures including total exercise time, myocardial perfusion, angina frequency and quality of life support a clinically meaningful biologic effect. This therapy warrants study in larger randomized studies.
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